Synthesis and in vitro cytotoxic activity of N‐, F‐, and S‐ether derivatives of podophyllotoxin fatty acid adducts

Mardenborough

et al. 2007

Isosteres of cryptolepine (1) were synthesized and evaluated for their antiinfective activities. Overall, the sulfur isostere, 5-methyl benzothieno [3,2-b]quinoline (5b) was equipotent to 1 and has shown no cytotoxicity at 23.8 μg/ml. Compound 5b was also found to have a broad spectrum of activity. Both the carbon and oxygen isosteres were less potent than cryptolepine. A limited library of 2-substituted analogs of 5b has been synthesized and evaluated in antifungal screens but did not show increase in potency compared to the unsubstituted 5b. Similarly, evaluation of tricyclic benzothieno [3,2-b]pyridines while showing promise in individual screens did not produce an overall increase in potency. Overall, the evaluation of the activities of 5b compared with standard antifungal/antiprotozoal agents suggests that the benzothienoquinoline scaffold could serve as a lead for optimization.Opportunistic infections are caused by pathogens that take advantage of a suppressed immune system. Such conditions as HIV AIDS disease, organ transplantation and long-term use of corticosteroids for example, cause either immune suppression or some disruption in the immune system. 1 With an estimated 40.3 million people living with AIDS around the globe 2 and the increasing development of resistance to current therapies, there is a continuing need for new antiinfective agents against opportunistic infections.Previous studies in our laboratories 3,4 and those of others 5 have indicated that cryptolepine and other alkyl-substituted indolo [3,2-b]quinolines possess interesting biological activities including antiinfective activity against several opportunistic infectious organisms (OIs). These include Candida albicans (Ca), Cryptoccocus neoformans (Cn), and Aspergillus fumigatus (Af). These actions of the indoloquinolines appear to operate through intercalation into DNA, binding preferentially at GC-rich sequences and stimulating DNA cleavage by human topoisomerase II. On the basis of these initial observations, we embarked on Structure-Activity Relationship (SAR) studies to probe and identify structural features that enhance the potency of the indoloquinoline scaffold.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem. Author manuscript; available in PMC 2008 January 15. Several publications from our laboratories have indicated that alkylation of the nitrogen at the 5 position is required for the antiinfective activities associated with the quindoline scaffold. 6,7 In particular, an ω-cycloalkyl pentyl group was associated with increased po...

Section: Cytotoxicity Assaymentioning

confidence: 99%

Synthesis and evaluation of isosteres of N-methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents

Mardenborough

et al. 2007

“…The assay was performed in 96-well tissue culture-treated microplates and compounds were tested up to a highest concentration of 23.8 μg/mL as described earlier 47. In brief, cells (25,000 cells/well) were seeded to the wells of the plate and incubated for 24 h. Samples were added and plates were again incubated for 48 h. The number of viable cells was determined by the neutral red assay as previously described 47. IC 50 values were determined from dose curves of growth inhibition versus concentration.…”

Section: Methodsmentioning

confidence: 99%

Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens

Boateng

Eyunni

et al. 2011

Self Cite

Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.

“…The assay was performed in 96-well tissue culture-treated microplates and compounds were tested up to a highest concentration of 10 mg/mL as described earlier. 23 In brief, cells (25,000 cells/well) were seeded to the wells of the plate and incubated for 24 h. Samples were added and plates were again incubated for 48 h. The number of viable cells was determined by the Neutral Red dye assay. IC50 values were determined from dose curves of growth inhibition versus concentration.…”

Section: Biological Activitymentioning

confidence: 99%

CoMFA studies and in vitro evaluation of some 3-substituted benzylthio quinolinium salts as anticryptococcal agents

Bolden

Boateng

et al. 2013

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The 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) molecular modeling technique or Comparative Molecular Field Analysis (CoMFA) has been used to design analogs of the natural product cryptolepine (1). Twenty-three compounds with their in vitro biological activities (IC50 values) against C. neoformans were used to generate the training set database of compounds for the CoMFA studies. The cross-validated q2, non-cross-validated r2, and partial least squares (PLS) analysis results were used to predict the biological activity of 11 newly designed test set compounds. The best CoMFA model produced a q2 of 0.815 and an r2 of 0.976 indicating high statistical significance as a predictive model. The steric and electrostatic contributions from the contour map were interpreted from the color-coded contour plots generated from the PLS model and the active structural components for potency against C. neoformans were determined and validated in the test set compounds. The 3-substituted benzylthio quinolinium salts (4) that make up the test set were synthesized and evaluated based on the predicted activity from the CoMFA model and the results produced a good correlation between the predicted and experimental activity (R = 0.82). Thus, CoMFA has served as an effective tool to aid the design of new analogs and in this case, it has aided the identification of compounds equipotent with amphotericin B, the gold standard in antifungal drug design.